Background
JNJ-63533054 is a potent and selective agonist of hGPR139 with an EC50 = 16nM[1,2]. JNJ-63533054 is an excellent candidate to explore the unknown in vivo function of central GPR139[3]
JNJ-63533054 specifically activated human GPR139 in the calcium mobilization (EC50=16±6nM) and GTPγS binding (EC50=17±4nM) assays[1]. JNJ-63533054 effectively binds and acts as an agonist to zebrafish GPR139 with EC50 of 3.91nM[4]
JNJ-63533054 activated the rat and mouse GPR139 receptor with similar potency (rat EC50=63±24nM, mouse EC50=28±7nM)[1]. JNJ-63533054(oral dose of 10mg/kg) crossed the blood-brain barrier in both male mice and male rats, and the brain to plasma ratio was close to 1 in mouse and slightly higher in rat. In the marble burying test, JNJ-63533054(10mg/kg p.o.) produced a small anxiolytic-like effect, with no interaction with fluoxetine, and no effect in elevated plus maze (EPM)[3]. Administration of a high dose (1μg/g BW) of JNJ-6353305 had no effect on locomotor activity, and fear response, but fear-conditioned place avoidance was diminished; zebrafish treated with a lower dose(0.1μg/g BW) of GPR139 agonist exhibited avoidance to the contextual compartments[4]. JNJ-63533054(oral dose of 3-30mg/kg) dose-dependently reduced non-rapid eye movement (NREM) latency and increased NREM sleep duration without altering rapid eye movement (REM) sleep when acutely administered at the beginning of the light phase. This effect progressively dissipated upon 7-day repeated dosing[5]. Systemic administration of JNJ-63533054 (30mg/kg, p.o.) reversed compulsive-like alcohol drinking and decreases withdrawal-induced hyperalgesia in alcohol-dependent rats that exhibit symptoms of alcohol dependence[6]
参考文献:
[1]. Liu C, Bonaventure P, et al. GPR139, an Orphan Receptor Highly Enriched in the Habenula and Septum, Is Activated by the Essential Amino Acids L-Tryptophan and L-Phenylalanine. Mol Pharmacol. 2015;88(5):911-925.
[2]. Dvorak CA, Coate H, et al. Identification and SAR of Glycine Benzamides as Potent Agonists for the GPR139 Receptor. ACS Med Chem Lett. 2015;6(9):1015-1018. Published 2015 Jul 20.
[3]. Shoblock JR, Welty N, et al. In vivo Characterization of a Selective, Orally Available, and Brain Penetrant Small Molecule GPR139 Agonist. Front Pharmacol. 2019;10:273. Published 2019 Mar 21.
[4]. Roy N, Ogawa S, et al. Habenula GPR139 is associated with fear learning in the zebrafish. Sci Rep. 2021;11(1):5549. Published 2021 Mar 10.
[5]. Wang L, Dugovic C, et al. Putative role of GPR139 on sleep modulation using pharmacological and genetic rodent models. Eur J Pharmacol. 2020;882:173256.
[6]. Kononoff J, Kallupi M, et al. Systemic and Intra-Habenular Activation of the Orphan G Protein-Coupled Receptor GPR139 Decreases Compulsive-Like Alcohol Drinking and Hyperalgesia in Alcohol-Dependent Rats. eNeuro. 2018;5(3):ENEURO.0153-18.2018. Published 2018 Jul 2.
JNJ-63533054 是一种有效的选择性 hGPR139 激动剂，EC50 = 16nM[1,2]。 JNJ-63533054 是探索中枢 GPR139 未知体内功能的极佳候选者[3]
JNJ-63533054 在钙动员 (EC50=16±6nM) 和 GTPγS 结合 (EC50=17±4nM) 测定中特异性激活人 GPR139[1]。 JNJ-63533054 有效结合并作为斑马鱼 GPR139 的激动剂，EC50 为 3.91nM[4]
JNJ-63533054 激活大鼠和小鼠 GPR139 受体具有相似的效力（大鼠 EC50=63±24nM，小鼠 EC50=28±7nM） [1]. JNJ-63533054(口服剂量10mg/kg)在雄性小鼠和雄性大鼠体内均可透过血脑屏障，小鼠脑浆比接近1，大鼠略高。在大理石掩埋试验中，JNJ-63533054(10mg/kg p.o.) 产生了轻微的抗焦虑样作用，与氟西汀没有相互作用，在高架十字迷宫 (EPM) 中也没有作用[3]。给予高剂量（1μg/g BW）的 JNJ-6353305 对运动活动和恐惧反应没有影响，但恐惧条件性位置回避减少；用较低剂量 (0.1μg/g BW) 的 GPR139 激动剂处理的斑马鱼表现出对上下文隔室的回避[4]。 JNJ-63533054（口服剂量为 3-30 毫克/千克）在光照阶段开始时急性给药时，剂量依赖性地减少非快速眼动 (NREM) 潜伏期并增加 NREM 睡眠持续时间，而不改变快速眼动 (REM) 睡眠.这种效果在重复给药 7 天后逐渐消失[5]。 JNJ-63533054（30mg/kg，口服）的全身给药可逆转表现出酒精依赖症状的酒精依赖大鼠的强迫性饮酒并减少戒断诱导的痛觉过敏[6]
Protocol
| Cell experiment [1]: |
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Cell lines
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HEK293-T cells expressing zebrafish GPR139
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Preparation Method
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The cells were serum starved in the media with 0.5% FBS for 18-20h, and then treated with the vehicle (control) or various concentrations of JNJ-63533054 in the media for 6h.
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Reaction Conditions
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4-128nM in 0.5% DMSO, 6h
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Applications
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JNJ-63533054 induced luciferase activity against zebrafish GPR139 in a concentration-dependent manner. For zebrafish GPR139, the maximal induction of 3.3-fold of vehicle control was achieved at a concentration of 128nM. From the dose-response curve, the half effective maximal concentration (EC50) values of JNJ-63533054 to zebrafish GPR139 was 3.91nM.
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| Animal experiment [2]: |
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Animal models
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Male Sprague-Dawley rats, 350-450g
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Preparation Method
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Separate groups of rats were orally dosed at 2 hours into the light phase with the GPR139 agonist JNJ-63533054 (3, 10, and 30mg/kg, n=8), its less active enantiomer JNJ-63770044 (10mg/kg, n=7), and L-Trp (200mg/kg, n=7) or vehicle (0.5% hydroxypropyl methylcellulose in suspension) administered in the same animals receiving each dose.
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Dosage form
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3, 10, and 30mg/kg, orally dosed
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Applications
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The results are presented for the first hour after dosing based on the short-lasting effects observed. Compared with vehicle, JNJ-63533054 induced a dose-dependent reduction in locomotor activity in the first hour after the treatment that reached significance from the dose of 10mg/kg onward. In contrast, at the same dose of 10mg/kg, its less active enantiomer did not modify locomotor activity. For comparison, L-Trp was tested in the same experimental conditions and spontaneous locomotor activity was not affected at 200mg/kg.
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参考文献:
[1]. Roy N, Ogawa S, et al. Habenula GPR139 is associated with fear learning in the zebrafish. Sci Rep. 2021;11(1):5549. Published 2021 Mar 10.
[2]. Liu C, Bonaventure P, et al. GPR139, an Orphan Receptor Highly Enriched in the Habenula and Septum, Is Activated by the Essential Amino Acids L-Tryptophan and L-Phenylalanine. Mol Pharmacol. 2015;88(5):911-925.
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